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Item Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial(Mary Ann Liebert, 2018-10-01) Hammond, Flora M.; Sherer, Mark; Malec, James F.; Zafonte, Ross D.; Dikmen, Sureyya; Bogner, Jennifer; Bell, Kathleen R.; Barber, Jason; Temkin, Nancy; Physical Medicine and Rehabilitation, School of MedicineDespite limited evidence to support the use of amantadine to enhance cognitive function after traumatic brain injury (TBI), the clinical use for this purpose is highly prevalent and is often based on inferred belief systems. The aim of this study was to assess effect of amantadine on cognition among individuals with a history of TBI and behavioral disturbance using a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice-daily versus placebo for 60 days. Included in the study were 119 individuals with two or more neuropsychological measures greater than 1 standard deviation below normative means from a larger study of 168 individuals with chronic TBI (>6 months post-injury) and irritability. Cognitive function was measured at treatment days 0, 28, and 60 with a battery of neuropsychological tests. Composite indices were generated: General Cognitive Index (included all measures), a Learning Memory Index (learning/memory measures), and Attention/Processing Speed Index (attention and executive function measures). Repeated-measures analysis of variance revealed statistically significant between-group differences favoring the placebo group at day 28 for General Cognitive Index (p = 0.002) and Learning Memory Index (p = 0.001), but not Attention/Processing Speed Index (p = 0.25), whereas no statistically significant between-group differences were found at day 60. There were no statistically significant between-group differences on adverse events. Cognitive function in individuals with chronic TBI is not improved by amantadine 100 mg twice-daily. In the first 28 days of use, amantadine may impede cognitive processing. However, the effect size was small and mean scores for both groups were generally within expectations for persons with history of complicated mild-to-severe TBI, suggesting that changes observed across assessments may not have functional significance. The use of amantadine to enhance cognitive function is not supported by these findings.Item Associations of brain-derived neurotrophic factor rs6265 polymorphism and cognitive function in breast cancer survivors from a cross-sectional study(Wiley, 2024) Goto, Taichi; Saligan, Leorey N.; Li, Xiaobai; Xiang, Lichen; Kwiat, Catherine; Nguyen, Christopher; Crouch, Adele; Von Ah, Diane; School of NursingBackground: Breast cancer survivors (BCS) often complain of cancer-related cognitive impairment (CRCI) during and even months after completing primary cancer treatments, particularly chemotherapy. The etiology of CRCI is unknown, but associations of CRCI with germline genetic polymorphisms have been reported, including Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism. The current study investigated the associations of specific BDNF rs6265 with CRCI. Methods: Cancer-related cognitive impairment was assessed using subjective reports of cognitive symptoms (the version 1.0, 8-item short-forms of the Patient-Reported Outcomes Measurement Information System®) and computerized objective cognitive function scores (CANTAB®). BDNF rs6265 genotypes were determined from buccal swabs. The associations of specific BDNF rs6265 with CRCI were examined by either one-way analysis of variance or the Kruskal–Wallis test followed by post hoc tests and rank-based regression analysis. Results: We examined 356 female BCS. The mean (SD) age was 55.6 (9.8) years old, the median (IQR) years since cancer diagnosis were 4.0 (6.0), and 331 (92.7%) were self-described as White. BCS carrying the Met/Met genotype showed poorer results on ‘visual episodic memory and new learning’ and ‘spatial working memory and executive function.’ This relationship was observed regardless of prior chemotherapy. Conclusion: Our findings suggest that carrying the BDNF rs6265 Met/Met genotype increases the risk for CRCI in BCS. These results are foundational in nature and provide important information to identify mechanisms underpinning CRCI.Item Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults(American Medical Association, 2023) Walters, Skylar; Contreras, Alex G.; Eissman, Jaclyn M.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Peterson, Amalia; Gifford, Katherine A.; Cuccaro, Michael L.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Genetics Consortium; Alzheimer’s Disease Sequencing Project; Radiology and Imaging Sciences, School of MedicineImportance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. Design, setting, and participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main outcomes and measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.Item Co-occurring Deficits in Clinical and Cognitive Insight in Prolonged Schizophrenia- Spectrum Disorders: Relationship to Metacognitive Deficits(Oxford University Press, 2021-07-20) Mervis, Joshua E.; Bonfils, Kelsey A.; Cooper, Samuel E.; Wiesepape, Courtney; Lysaker, Paul H.; Psychiatry, School of MedicinePeople diagnosed with schizophrenia have been broadly observed to experience deficits in clinical and cognitive insight; however, less is understood about how these deficits are related. One possibility is that these deficits co-occur among people when other deficits in cognition are present, such as in executive function, social cognition, and metacognition, which may either promote the development of both forms of poor insight or allow one to negatively influence the other. To explore this possibility, we conducted a cluster analysis using assessments of clinical and cognitive insight among 95 adults with a schizophrenia spectrum disorder. As predicted, this analysis yielded a group with concurrently poor clinical and cognitive insight (n = 36). Additional groups were found with concurrently good clinical and cognitive insight (n = 28) and poor clinical insight and good cognitive insight (n = 31). Groups were then compared on assessments of executive function, social cognition, and metacognition. The group with concurrently lower levels of cognitive and clinical insight had significantly poorer metacognition relative to the other groups. In particular, they tended to form more fragmented and less integrated ideas about themselves and others. No differences were found for executive function or social cognition. The result may suggest that while clinical and cognitive insight is partially orthogonal phenomena, relatively lower levels of metacognition, or difficulties forming integrated ideas about oneself and others, maybe a condition leading to the confluence of lower clinical and cognitive insight. Interventions targeting metacognition may be of particular use for this group.Item Correction: Neural correlates of automatic emotion regulation and their association with suicidal ideation in adolescents during the first 90-days of residential care(Springer Nature, 2024-02-19) Dobbertin, Matthew; Blair, Karina S.; Aloi, Joseph; Bajaj, Sahil; Bashford-Largo, Johannah; Mathur, Avantika; Zhang, Ru; Carollo, Erin; Schwartz, Amanda; Elowsky, Jaimie; Ringle, J. L.; Tyler, Patrick; Blair, R. James; Psychiatry, School of MedicineCorrection to: Translational Psychiatry 10.1038/s41398-023-02723-9, published online 23 January 2024 In this article, the affiliation details for Author Sahil Bajaj were incorrectly given as “Department of Cancer Systems Imaging, MD Anderson Center, South Campus Research Bldg, Houston, TX, USA” but should have been “Department of Cancer Systems Imaging, MD Anderson Cancer Center, Houston, TX, USA” The original article has been corrected.Item Family Environment in Children With Hearing Aids and Cochlear Implants: Associations With Spoken Language, Psychosocial Functioning, and Cognitive Development(Wolters Kluwer, 2020) Frush Holt, Rachael; Beer, Jessica; Kronenberger, William G.; Pisoni, David B.; Lalonde, Kaylah; Mulinaro, Lindsay; Otolaryngology -- Head and Neck Surgery, School of MedicineObjectives: To examine differences in family environment and associations between family environment and key speech, language, and cognitive outcomes in samples of children with normal hearing and deaf and hard-of-hearing (DHH) children who use hearing aids and cochlear implants. Design: Thirty families of children with normal hearing (n = 10), hearing aids (n = 10), or cochlear implants (n = 10) completed questionnaires evaluating executive function, social skills, and problem behaviors. Children's language and receptive vocabulary were evaluated using standardized measures in the children's homes. In addition, families were administered a standardized in-home questionnaire and observational assessment regarding the home environment. Results: Family environment overall was similar across hearing level and sensory aid, although some differences were found on parental responsivity and physical environment. The level of supportiveness and enrichment within family relationships accounted for much of the relations between family environment and the psychosocial and neurocognitive development of DHH children. In contrast, the availability of objects and experiences to stimulate learning in the home was related to the development of spoken language. Conclusions: Whereas broad characteristics of the family environments of DHH children may not differ from those of hearing children, variability in family functioning is related to DHH children's at-risk speech, language, and cognitive outcomes. Results support the importance of further research to clarify and explain these relations, which might suggest novel methods and targets of family-based interventions to improve developmental outcomes.Item Family-Level Executive Functioning and At-Risk Pediatric Hearing Loss Outcomes(American Speech-Language-Hearing Association, 2021) Blank, Andrew; Frush Holt, Rachael; Pisoni, David B.; Kronenberger, William G.; Otolaryngology -- Head and Neck Surgery, School of MedicinePurpose: Using a new measure of family-level executive functioning (EF; the Family Characteristics Scale [FCS]), we investigated associations between family-level EF, spoken language, and neurocognitive skills in children with hearing loss (HL), compared to children with normal hearing. Method: Parents of children with HL (n = 61) or children with normal hearing (n = 65) completed the FCS-Parent, and clinicians evaluated families using the FCS-Examiner. Children completed an age-appropriate version of the Concepts and Following Directions subtest of the Clinical Evaluation of Language Fundamentals and the Peabody Picture Vocabulary Test–Fourth Edition. Child EF was assessed via the parent report Behavior Rating Inventory of Executive Function. Results: Two higher order components were derived from FCS subscales: Family Inhibition and Family Organization. For both samples, Family Inhibition was positively associated with child inhibition, child shifting, and child language comprehension skills. Family Organization was differentially associated with child inhibition, working memory, and planning/organization skills across the samples. Additionally, Family Inhibition was associated with child planning and organization skills for children with HL. Conclusions: Results support the FCS as a measure of family-level EF. Family-level inhibition related to better child inhibition, flexibility/shifting, and language comprehension across both samples and to better planning and organization skills in children with HL. As children with HL experienced greater difficulties in EF, families demonstrated greater organization, possibly as a compensatory measure. Results suggest that inhibition and organization at a family level may be important targets for the development of novel interventions to promote EF and language outcomes for children with HL.Item Longitudinal cognitive performance of Alzheimer's disease neuropathological subtypes(Alzheimer’s Association, 2021-09-27) Uretsky, Madeline; Gibbons, Laura E.; Mukherjee, Shubhabrata; Trittschuh, Emily H.; Fardo, David W.; Boyle, Patricia A.; Keene, C. Dirk; Saykin, Andrew J.; Crane, Paul K.; Schneider, Julie A.; Mez, Jesse; Radiology and Imaging Sciences, School of MedicineIntroduction: Alzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments. Methods: Two hundred ninety-two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed-effects models that included subtype, time, and a subtype-time interaction as predictors and four cognitive domain factor scores (memory, executive function, language, visuospatial) and a global score as outcomes. To assess if memory was relatively preserved in HpSpAD, non-memory factor scores were included as covariates in the mixed-effects model with memory as the outcome. Results: There were 57 (20%) with lpAD, 22 (8%) with HpSpAD and 213 (73%) with tAD. LpAD died significantly later than the participants with tAD (2.4 years, P = .01) and with HpSpAD (3.8 years, P = .03). Compared to tAD, HpSpAD, but not lpAD, performed significantly worse in all cognitive domains at the time of initial impairment and declined significantly faster in memory, language, and globally. HpSpAD did not have relatively preserved memory performance at any time point. Conclusion: The relative frequencies of AD neuropathological subtypes in an epidemiological sample were consistent with a previous report in a convenience sample. People with HpSpAD decline rapidly, but may not have a memory-sparing clinical syndrome. Cohort-specific differences in regional tau burden and comorbid neuropathology may explain the lack of clinicopathological correlation.Item Neural correlates of automatic emotion regulation and their association with suicidal ideation in adolescents during the first 90-days of residential care(Springer Nature, 2024-01-23) Dobbertin, Matthew; Blair, Karina S.; Aloi, Joseph; Bajaj, Sahil; Bashford-Largo, Johannah; Mathur, Avantika; Zhang, Ru; Carollo, Erin; Schwartz, Amanda; Elowsky, Jaimie; Ringle, J. L.; Tyler, Patrick; Blair, R. James; Psychiatry, School of MedicineBackground: Suicide is the second leading cause of death for adolescents in the United States. However, relatively little is known about the forms of atypical neuro-cognitive function that are correlates of suicidal ideation (SI). One form of cognitive/affective function that, when dysfunctional, is associated with SI is emotion regulation. However, very little work has investigated the neural correlates of emotion dysregulation in adolescents with SI. Methods: Participants (N = 111 aged 12-18, 32 females, 31 [27.9%] reporting SI) were recruited shortly after their arrival at a residential care facility where they had been referred for behavioral and mental health problems. Daily reports of SI were collected during the participants' first 90-days in residential care. Participants were presented with a task-fMRI measure of emotion regulation - the Affective Number Stroop task shortly after recruitment. Participants were divided into two groups matched for age, sex and IQ based on whether they demonstrated SI. Results: Participants who demonstrated SI showed increased recruitment of regions including dorsomedial prefrontal cortex/supplemental motor area and parietal cortex during task (congruent and incongruent) relative to view trials in the context of emotional relative to neutral distracters. Conclusions: Participants with SI showed increased recruitment of regions implicated in executive control during the performance of a task indexing automatic emotion regulation. Such data might suggest a relative inefficiency in the recruitment of these regions in individuals with SI.Item Questionnaire-based assessment of executive functioning: Case studies(Taylor & Francis, 2018-01) Kronenberger, William G.; Castellanos, Irina; Pisoni, David B.; Psychiatry, School of MedicineDelays in the development of executive functioning skills are frequently observed in pediatric neuropsychology populations and can have a broad and significant impact on quality of life. As a result, assessment of executive functioning is often relevant for the development of formulations and recommendations in pediatric neuropsychology clinical work. Questionnaire-based measures of executive functioning behaviors in everyday life have unique advantages and complement traditional neuropsychological measures of executive functioning. Two case studies of children with spina bifida are presented to illustrate the clinical use of a new questionnaire measure of executive and learning-related functioning, the Learning, Executive, and Attention Functioning Scale (LEAF). The LEAF emphasizes clinical utility in assessment by incorporating four characteristics: brevity in administration, breadth of additional relevant content, efficiency of scoring and interpretation, and ease of availability for use. LEAF results were consistent with another executive functioning checklist in documenting everyday behavior problems related to working memory, planning, and organization while offering additional breadth of assessment of domains such as attention, processing speed, and novel problem-solving. These case study results demonstrate the clinical utility of questionnaire-based measurement of executive functioning in pediatric neuropsychology and provide a new measure for accomplishing this goal.